Randomized clinical trials show that aerobic exercise training improves glycemic control in patients with type 2 diabetes mellitus (T2DM).1 However, interindividual variability is large.2 This may be explained by genetic variability,3 but ambient hyperglycemia4 and pancreatic β-cell function5 may also contribute. We examined whether changes in glycemic control following a 12- to 16-week aerobic exercise training intervention were influenced by the pretraining glycemic state in 105 individuals with impaired glucose tolerance or T2DM.

DISCUSSION

These findings emphasize that exercise-induced improvements in glycemic control are dependent on the pretraining glycemic level. We demonstrate that although moderate-intensity aerobic exercise can improve glycemic control, individuals with ambient hyperglycemia are the most likely to be nonresponders. Our key observation is that pretraining hyperglycemia predicts exercise-induced improvements in glycemic control: for every 1-mmol/L rise in pretraining 2-hour OGTT glucose level above 13.1-mmol/L (the curve inflection point in Figure, A) we predict a 0.2-mmol/L loss of improvement in 2-hour OGTT glucose following exercise. Accordingly, for every 1–percentage-point increase in pretraining HbA1c level above 6.2% (the curve inflection point in Figure, B), we predict a 0.2% point loss of improvement in HbA1c level following exercise. Pretraining hyperglycemia also predicted the exercise-induced increment in aerobic fitness: for a 1–percentage-point increase in pretraining HbA1c level, we predict a 0.11 L/min loss of improvement in V̇o2max following exercise.

Prior work shows that diabetes remission following exercise and diet intervention is more likely in individuals with a shorter disease history and lower HbA1c level.6 We show that aerobic exercise-induced improvements in glycemic control are blunted by ambient hyperglycemia, particularly in subjects with T2DM. Mechanistic studies are required to help us understand this phenomenon, but underlying impairments in β-cell function are likely to be very important.5 That hyperglycemia blunted the cardiovascular adaptations to exercise (V̇o2max) is in agreement with some prior reports7 and may be explained by the causal association between chronic hyperglycemia and microvascular and macrovascular dysfunction.8

The clinical relevance of these new findings is paramount and highlights the need to understand the metabolic “nonresponder.” Because chronic hyperglycemia (>6.2% HbA1c level; >13.1-mmol/L glucose level) potentially predicts a poor therapeutic effect of aerobic exercise on glycemic control and fitness, using exercise to treat patients with poorly controlled T2DM may have limited chances of a successful outcome.

Author Contributions: Dr Solomon had access to the data and takes responsibility for the integrity of the data and the accuracy of the analysis.

Study concept and design: Solomon, Kirwan.

Acquisition of data: Solomon, Karstoft, Haus, Kirwan.

Analysis and interpretation of data: All authors.

Drafting of the manuscript: Solomon, Malin, Kirwan.

Critical revision of the manuscript for important intellectual content: All authors.

Statistical analysis: Solomon, Malin.

Obtained funding: Solomon, Malin, Kirwan.

Administrative, technical, and material support: All authors.

Study supervision: Solomon, Kirwan.

Conflict of Interest Disclosures: None reported.

Funding/Support: The study was funded by a Paul Langerhans program grant from the European Foundation for the Study of Diabetes (Dr Solomon) and was supported by grant RO1 AG12834 from the National Institute of Health (Dr Kirwan) and Clinical and Translational Science Award UL1 RR024989. Dr Malin was supported by NIH grant T32 DK007319.

Role of the Sponsors: The funding sources played no role in the study design; in the collection, analysis, and interpretation of data; in the writing of the report; or in the decision to submit the article for publication.

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